EP1867331A1 - Triazol-derivat und seine verwendung - Google Patents

Triazol-derivat und seine verwendung Download PDF

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Publication number
EP1867331A1
EP1867331A1 EP06731733A EP06731733A EP1867331A1 EP 1867331 A1 EP1867331 A1 EP 1867331A1 EP 06731733 A EP06731733 A EP 06731733A EP 06731733 A EP06731733 A EP 06731733A EP 1867331 A1 EP1867331 A1 EP 1867331A1
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Prior art keywords
optionally substituted
ring
optionally
phenyl
compound
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English (en)
French (fr)
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EP1867331A4 (de
Inventor
Keiji c/o TAKEDA PHARMACEUTICAL COMPANY KUBO
Mamoru Tobisu
Eiji c/o TAKEDA PHARMACEUTICAL COMPANY HONDA
Takahiko c/o TAKEDA PHARMACEUTICAL TANIGUCHI
Yoshiyuki c/o TAKEDA PHARMACEUTICAL FUKASE
Masaki c/o TAKEDA PHARMACEUTICAL KAWAMURA
Masaharu c/o TAKEDA PHARMACEUTICAL NAKAYAMA
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of EP1867331A1 publication Critical patent/EP1867331A1/de
Publication of EP1867331A4 publication Critical patent/EP1867331A4/de
Withdrawn legal-status Critical Current

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Definitions

  • the present invention relates to a novel triazole derivative having a thrombin receptor antagonistic action and useful for the prophylaxis or treatment of thrombosis, vascular restenosis, cerebral infarction, heart disease, disseminated intravascular coagulation syndrome, neurologic disease and/or malignant tumor and the like and use thereof.
  • thrombin not only functions as a final protease of coagulation cascade, which catalyzes the decomposition of fibrinogen to produce fibrin, but is also a multifunctional molecule that acts on various cells including platelet. While involvement of a "thrombin receptor" in such cell response has been presumed, and biochemical investigations relating to receptor characteristics in the platelet have been continued, the substance of the molecule has remained unknown. In 1990, a report documented thrombin receptor expression and receptor signaling by injecting human umbilical vein endothelial mRNA into Rana catesbeiana oocyte, showing the similarity to vascular endothelial expression thrombin receptor that had been reported.
  • a triazole derivative having a particular structure is described to have, for example, an FXa inhibitory action in WO99/32454 , a glycine transporter inhibitory action in DE10315570A1 , and a cytokine inhibitory activity in WO2004/050642 .
  • the derivative is not described or suggested to have a thrombin receptor antagonistic action, and is different from the triazole derivative of the present invention in the structural characteristics.
  • a 1,2,3-triazole derivative having a particular structure has high affinity for a thrombin receptor (particularly PAR-1) and a strong antagonistic action thereon, can exhibit a sustained and sufficient effect by oral administration, and is useful as a pharmaceutical agent for the prophylaxis and/or treatment of a disease involving PAR-1 (for example, thrombosis, vascular restenosis, cerebral infarction, heart disease, disseminated intravascular coagulation syndrome, neurologic disease, malignant tumor and the like) and the like.
  • a disease involving PAR-1 for example, thrombosis, vascular restenosis, cerebral infarction, heart disease, disseminated intravascular coagulation syndrome, neurologic disease, malignant tumor and the like
  • a 1,2,3-triazole derivative represented by the following formula (I) and a salt thereof have a strong thrombin receptor (particularly PAR-1) antagonistic action, high safety, and a sustained and sufficient effect by oral administration, which resulted in the completion of the present invention.
  • the present invention relates to
  • R 1a and R 1b are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted alkoxy.
  • alkyl examples include C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylpropyl, etc., and the like.
  • alkenyl examples include C 2-6 alkenyl such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc., and the like.
  • alkenyl examples include C 2-6 alkenyl such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2
  • alkynyl examples include C 2-6 alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc., and the like.
  • aromatic hydrocarbon group examples include monocyclic or condensed polycyclic aromatic hydrocarbon group, such as C 6-14 aromatic hydrocarbon group (e.g., phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc.) and the like.
  • cycloalkyl examples include C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and the like.
  • cycloalkenyl examples include C 3-7 cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc., and the like.
  • aralkyl examples include C 7-16 aralkyl such as phenyl-C 1-6 alkyl (e.g., benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.), naphthyl-C 1-6 alkyl (e.g., (1-naphthyl)methyl, (2-naphthyl)methyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, etc.) and the like, and the like.
  • phenyl-C 1-6 alkyl e.g., benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.
  • naphthyl-C 1-6 alkyl e.g., (1-naphthyl)methyl, (2-na
  • cycloalkylalkyl examples include C 3-7 cycloalkyl-C 1-6 alkyl such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, etc., and the like.
  • arylalkenyl examples include C 6-14 aryl-C 2-6 alkenyl such as phenyl-C 2-6 alkenyl (e.g., 2-phenylvinyl, 3-phenyl-1-propenyl, 3-phenyl-2-propenyl, etc.), naphthyl-C 2-6 alkenyl (e.g., 2-(1-naphthyl)vinyl, 2-(2-naphthyl)vinyl, 3-(1-naphthyl)-1-propenyl, 3-(1-naphthyl)-2-propenyl, 3-(2-naphthyl)-1-propenyl, 3-(2-naphthyl)-2-propenyl, etc.) and the like, and the like.
  • phenyl-C 2-6 alkenyl e.g., 2-phenylvinyl, 3-phenyl-1-propenyl, 3-phenyl
  • cycloalkyl condensed with benzene ring examples include C 5-7 cycloalkyl condensed with benzene ring such as indanyl, 1,2,3,4-tetrahydronaphthyl, etc., and the like.
  • bridged cyclic hydrocarbon group examples include C 7-10 bridged cyclic hydrocarbon group such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantly, etc., and the like,
  • heterocyclic group of the "optionally substituted heterocyclic group” for R 1a or R 1b examples include aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like containing, as a ring-constituting atom (ring atom), at least one (preferably 1 to 4, more preferably 1 or 2) heteroatoms of one to three kinds (preferably one or two kinds) selected from oxygen atom, sulfur atom and nitrogen atom and the like.
  • aromatic heterocyclic group examples include 5-or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and 8- to 16-membered (preferably, 8- to 12-membered) aromatic fused heterocyclic group such as benzofuranyl, isobenz
  • non-aromatic heterocyclic group examples include a heterocyclic group wherein 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic monocyclic heterocyclic group (aliphatic monocyclic heterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, perhydroazepinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl and the like; a heterocyclic group wherein the aforementioned 1 or 2 (preferably 1) non-aromatic monocyclic heterocyclic groups are condensed with 1 or 2 (preferably 1) benzen
  • heterocyclic group of the “optionally substituted heterocyclic group” optionally has, groups similar to the substituents that the aforementioned hydrocarbon group of the "optionally substituted hydrocarbon group” for R 1a or R 1b optionally has and the like can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • alkoxy of the "optionally substituted alkoxy” for R 1a or R 1b examples include C 1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 2-ethylpropyloxy and the like.
  • substituent that the "alkoxy” optionally has, groups similar to the substituents that the hydrocarbon group of the "optionally substituted hydrocarbon group" for R 1a or R 1b optionally has (preferably, halogen atom, hydroxy, oxo, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, optionally halogenated phenyl and the like) can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • R 1a and R 1b are optionally bonded to each other to form an optionally substituted nitrogen-containing non-aromatic heterocycle.
  • nitrogen-containing non-aromatic heterocycle of the "optionally substituted nitrogen-containing non-aromatic heterocycle” optionally formed by R 1a and R 1b bonded to each other, for example, 3- to 8-membered (preferably 4- to 6-membered) saturated or unsaturated (preferably saturated) nitrogen-containing non-aromatic monocyclic heterocycle (nitrogen-containing aliphatic monocyclic heterocycle) such as aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine, piperazine, oxazolidine, thiazolidine and the like, and the like can be mentioned.
  • the nitrogen-containing non-aromatic heterocycle may be nitrogen-containing non-aromatic fused heterocycle (e.g., 1,3,4,9-tetrahydro-2H- ⁇ -carboline) wherein the aforementioned nitrogen-containing non-aromatic monocyclic heterocycle is condensed with other ring such as benzene ring, pyridine ring, indole ring and the like.
  • nitrogen-containing non-aromatic fused heterocycle e.g., 1,3,4,9-tetrahydro-2H- ⁇ -carboline
  • substituent that the "nitrogen-containing non-aromatic heterocycle” optionally has, groups similar to the substituents that the hydrocarbon group of the "optionally substituted hydrocarbon group" for R 1a or R 1b optionally has (preferably, halogen atom, hydroxy, oxo, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, phenyl (the phenyl is optionally substituted by 1 to 5 substituents selected from halogen atom, hydroxy, C 1-4 alkoxy and the like), C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy-C 1-4 alkyl, optionally halogenated C 1-4 alkylsulfonyl, 4- to 7-membered cyclic amino (e.g., piperidino), 5- to 10-membered hetero
  • hydrocarbon group of the "optionally substituted hydrocarbon group” for R 1a or R 1b C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aromatic hydrocarbon group, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 7-16 aralkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 5-7 cycloalkyl condensed with benzene ring or C 7-10 bridged cyclic hydrocarbon group is preferable.
  • C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 7-16 aralkyl and C 5-7 cycloalkyl condensed with benzene ring are each optionally substituted by 1 to 3 substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, 5- to 10-membered heterocyclic group (e.g., pyridyl, pyrazinyl, indolyl, tetrahydrofuryl and the like; the heterocyclic group is optionally substituted by 1 to 3 substituents selected from C 1-4 alkyl, C 1-4 alkoxy and the like), optionally halogenated straight chain or branched C 1-4 alkylenedi
  • heterocyclic group of the "optionally substituted heterocyclic group” for R 1a or R 1b 5- or 6-membered aromatic monocyclic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from oxygen atom, sulfur atom and nitrogen atom (e.g., isoxazolyl, pyridyl); 3- to 8-membered saturated or unsaturated non-aromatic monocyclic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from oxygen atom, sulfur atom and nitrogen atom (e.g., pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, perhydroazepinyl, isoxazolidinyl); 8- to 12-membered aromatic fused heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from oxygen atom, sulfur atom and nitrogen atom, or non-aromatic fused hetero
  • substituents that the "heterocyclic group” optionally has include 1 to 5 (preferably 1 to 3) substituents selected from C 1-4 alkyl, phenyl-C 1-4 alkyl, phenoxy optionally substituted by 1 to 3 halogen atoms, oxo and the like.
  • nitrogen-containing non-aromatic heterocycle of the "optionally substituted nitrogen-containing non-aromatic heterocycle” optionally formed by R 1a and R 1b bonded to each other, 1,3,4,9-tetrahydro-2H- ⁇ -carboline, pyrrolidine, piperidine, piperazine, thiazolidine and the like are preferable.
  • the substituents that the "nitrogen-containing non-aromatic heterocycle" optionally has include 1 to 5 (preferably 1 to 3) substituents selected from hydroxy, oxo, carbamoyl, phenyl (the phenyl is optionally substituted by 1 to 5 substituents selected from halogen atom, hydroxy, C 1-4 alkoxy and the like), C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy-C 1-4 alkyl, optionally halogenated C 1-4 alkylsulfonyl, 4- to 7-membered cyclic amino (e.g., piperidino), 5- to 10-membered heterocyclyl-carbonylamino (e.g., 2- or 3-thienylcarbonylamino; the heterocyclyl is optionally substituted by 1 to 3 substituents selected from halogen atom, C 1-4 alkyl, C 1-4 alkoxy, etc.) and the like.
  • substituents selected from hydroxy,
  • alkoxy of the "optionally substituted alkoxy" for R 1a or R 1b , C 1-6 alkoxy is preferable.
  • substituent that the "alkoxy" optionally has include optionally halogenated phenyl (e.g., phenyl, fluorophenyl, chlorophenyl, bromophenyl, pentafluorophenyl, etc.) and the like.
  • halogenated phenyl e.g., phenyl, fluorophenyl, chlorophenyl, bromophenyl, pentafluorophenyl, etc.
  • R 1a a hydrogen atom and C 1-6 alkyl are preferable, and a hydrogen atom is more preferable.
  • optionally substituted cycloalkyl is preferable, C 3-7 cycloalkyl (the C 3-7 cycloalkyl is optionally substituted by 1 to 3 substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino and the like) is particularly preferable, and cyclopropyl is especially preferable.
  • R 2 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted alkoxy.
  • hydrocarbon group of the "optionally substituted hydrocarbon group” for R 2 a group similar to the "hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be mentioned.
  • heterocyclic group of the “optionally substituted heterocyclic group” for R 2 groups similar to the “heterocyclic group” of the “optionally substituted heterocyclic group” for R 1a or R 1b and the like can be mentioned.
  • heterocyclic group optionally has, groups similar to the substituents that the "hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b optionally has and the like can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • substituent that the "alkoxy” optionally has, groups similar to the substituents that the "hydrocarbon group" of the "optionally substituted hydrocarbon group” for R 1a or R 1b optionally has (preferably halogen atom, hydroxy, oxo, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, optionally halogenated phenyl and the like) can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • R 2 a hydrogen atom, "optionally substituted chain hydrocarbon group", aromatic hydrocarbon group, aralkyl, cycloalkylalkyl or arylalkenyl is preferable, a hydrogen atom or "optionally substituted chain hydrocarbon group” is more preferable, and "optionally substituted chain hydrocarbon group” is particularly preferable.
  • chain hydrocarbon group of the "optionally substituted chain hydrocarbon group” include alkyl, alkenyl, alkynyl and the like.
  • alkyl groups similar to the “alkyl” exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be used, and C 1-6 alkyl is preferable.
  • alkenyl groups similar to the “alkenyl” exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be used, and C 2-6 alkenyl is preferable.
  • alkynyl groups similar to the “alkynyl” exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be used, and C 2-6 alkynyl is preferable.
  • aromatic hydrocarbon group groups similar to the "aromatic hydrocarbon group” exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be used, and phenyl is preferable.
  • aralkyl groups similar to the “aralkyl” exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be used, and phenyl-C 1-6 alkyl is preferable.
  • cycloalkylalkyl groups similar to the “cycloalkylalkyl” exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be used, and C 3-7 cycloalkyl-C 1-6 alkyl is preferable.
  • arylalkenyl groups similar to the “arylalkenyl” exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b and the like can be used, and phenyl-C 2-6 alkenyl is preferable.
  • substituents that the "heterocyclic group” optionally has include 1 to 5 (preferably 1 to 3) substituents selected from halogen atom, C 1-4 alkyl and the like.
  • alkoxy of the "optionally substituted alkoxy" for R 2 , C 1-6 alkoxy is preferable.
  • substituent that the "alkoxy" optionally has include optionally halogenated phenyl (e.g., phenyl, fluorophenyl, chlorophenyl, bromophenyl, pentafluorophenyl and the like) and the like.
  • optionally halogenated phenyl e.g., phenyl, fluorophenyl, chlorophenyl, bromophenyl, pentafluorophenyl and the like
  • R 2 hydrogen atom, C 1-6 alkyl or C 2-6 alkenyl (the C 1-6 alkyl and the C 2-6 alkenyl are each optionally substituted by halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, optionally halogenated phenoxy and the like) is preferable, and a hydrogen atom, optionally halogenated C 1-6 alkyl or C 2-6 alkenyl is particularly preferable.
  • R 3 is a group represented by the formula -NHCOR 4 , -NHSO 2 R 5 , -NHCON(R 6a )(R 6b ), -NHCOOR 7 or -CONHR 8 , wherein R 4 and R 7 are each independently a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, and R 5 , R 6a , R 6b and R 8 are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted alkoxy.
  • heterocyclic group of the “optionally substituted heterocyclic group” for R 4 , R 5 , R 6a , R 6b , R 7 or R 8 a group similar to the "heterocyclic group” of the “optionally substituted heterocyclic group” for R 1a or R 1b and the like can be mentioned.
  • heterocyclic group optionally has, groups similar to the substituents that the “heterocyclic group” of the “optionally substituted heterocyclic group” for R 1a or R 1b optionally has and the like can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • alkoxy of the "optionally substituted alkoxy" for R 5 , R 6a , R 6b or R 8 for example, C 1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, etc., and the like can be used. Of these, C 1-3 alkoxy such as methoxy, ethoxy, propoxy and isopropoxy is preferable.
  • R 8 and the substituent on ring A (or ring A') are optionally bonded to each other to form an optionally substituted ring.
  • 5-to 8-membered (preferably 5- or 6-membered) heterocycle which contains one nitrogen atom, and further may contain 1 or 2 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom can be mentioned.
  • substituent that the ring formed by R 8 and the substituent on ring A (or ring A') bonded to each other optionally has, a group similar to the substituent that the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R 1a or R 1b optionally has (preferably, halogen atom, hydroxy, oxo, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino and the like) can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • R 6a and R 6b are optionally bonded to each other to form an optionally substituted nitrogen-containing non-aromatic heterocycle.
  • nitrogen-containing non-aromatic heterocycle of the "optionally substituted nitrogen-containing non-aromatic heterocycle” that can be formed by R 6a and R 6b bonded to each other
  • a ring similar to the "nitrogen-containing non-aromatic heterocycle" of the "optionally substituted nitrogen-containing non-aromatic heterocycle” that can be formed by R 1a and R 1b bonded to each other and the like can be used.
  • substituents that the "nitrogen-containing non-aromatic heterocycle” optionally has, groups similar to the substituents that the "hydrocarbon group" of the "optionally substituted hydrocarbon group” for R 1a or R 1b optionally has (preferably, halogen atom, hydroxy, oxo, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino and the like) and the like can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • R 4 and R 7 are each preferably hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, phenyl, C 3-7 cycloalkyl or phenyl-C 1-6 alkyl (the C 1-6 alkyl, C 2-6 alkenyl, phenyl, C 3-7 cycloalkyl and phenyl-C 1-6 alkyl are each optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, 4- to 6-membered cyclic amino (the 4- to 6-membered cyclic amino is optionally substituted by C 1-4 alkyl),
  • C 1-6 alkanoylamino optionally halogenated C 1-6 alkoxy-carbonylamino, optionally halogenated C 1-4 alkylthio, optionally halogenated C 1-4 alkylsulfinyl, optionally halogenated C 1-4 alkylsulfonyl, 5- to 10-membered heterocyclic group (preferably, thienyl, furyl and the like) and the like).
  • R 5 , R 6a , R 6b and R 8 are each preferably hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, phenyl, C 3-7 cycloalkyl, phenyl-C 1-6 alkyl or C 1-6 alkoxy (the C 1-6 alkyl, C 2-6 alkenyl, phenyl, C 3-7 cycloalkyl, phenyl-C 1-6 alkyl and C 1-6 alkoxy are each optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, optionally halogenated benzyloxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, 4- to 6-membered cyclic amino (the 4- to 6-membered cyclic amino is optionally substituted by C 1-4 alkyl), C 1-6 alkano
  • C 1-6 alkyl, C 2-6 alkenyl, phenyl or C 3-7 cycloalkyl (the C 1-6 alkyl, C 2-6 alkenyl, phenyl and C 3-7 cycloalkyl are each optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, C 1-6 alkanoylamino, optionally halogenated C 1-6 alkoxy-carbonylamino, optionally halogenated C 1-4 alkylthio, optionally halogenated C 1-4 alkylsulfinyl, optionally halogenated C 1-4 alkylsulfonyl, thienyl and the like) is more preferable.
  • R 4 trifluoromethyl, 2,2,2-trifluor
  • a hydrogen atom or C 1-6 alkyl is more preferable, and a hydrogen atom is particularly preferable.
  • a hydrogen atom, C 1-6 alkyl, phenyl, phenyl-C 1-6 alkyl or C 1-6 alkoxy (the C 1-6 alkyl, phenyl and phenyl-C 1-6 alkyl are each optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from halogen atom and optionally halogenated C 1-4 alkoxy and the like) is more preferable.
  • the "optionally substituted alkyl” is preferable, and C 1-6 alkyl is more preferable.
  • R 3 a group represented by the formula -CONHR 8 is preferable, and as the R 8 , the "optionally substituted chain hydrocarbon group” is preferable.
  • chain hydrocarbon group" of the “optionally substituted chain hydrocarbon group a group similar to the "chain hydrocarbon group” as a preferable example of the “optionally substituted chain hydrocarbon group” for R 2 and the like can be mentioned.
  • C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl-C 1-6 alkyl or C 1-6 alkoxy are each optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, carbamoyl, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, 4- to 6-membered cyclic amino (e.g., piperidino, morpholino, 1-piperazinyl and the like; the 4- to 6-membered cyclic amino is optionally substituted by C 1-4 alkyl), furyl and the like) is preferable, C 1-6 alkyl optionally substituted by 1
  • ring A is a monocyclic aromatic ring optionally having further substituent(s).
  • the "monocyclic aromatic ring" of the “monocyclic aromatic ring optionally further having substituent(s)" for ring A for example, (i) benzene ring and (ii) aromatic monocyclic heterocycle containing, besides carbon atom, preferably 1 to 3 heteroatoms of one or two kinds selected from nitrogen atom, sulfur atom and oxygen atom and the like can be mentioned.
  • aromatic monocyclic heterocycle examples include 5- to 6-membered aromatic monocyclic heterocycle such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc., and the like.
  • substituents that the "monocyclic aromatic ring” optionally has groups substitutable on the aromatic ring among the substituents that the "hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1a or R 1b optionally has and the like can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • the "monocyclic aromatic ring” optionally has, halogen atom, hydroxy, optionally halogenated C 1-4 alkyl, optionally halogenated C 1-6 alkoxy, C 2-6 alkenyloxy, amino, mono- or di-C 1-4 alkylamino, optionally halogenated phenyl-C 1-4 alkoxy, optionally halogenated phenoxy-C 1-4 alkoxy, optionally halogenated phenyl-C 1-4 alkyl-C 1-4 alkoxy and the like are more preferable, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • ring A' is a benzene ring optionally further having substituent(s) or 6-membered nitrogen-containing aromatic heterocycle (e.g., pyridine, pyridazine, pyrimidine, pyrazine, triazine etc.) optionally further having substituent(s).
  • substituent(s) or 6-membered nitrogen-containing aromatic heterocycle e.g., pyridine, pyridazine, pyrimidine, pyrazine, triazine etc.
  • ring A As the ring A, ring A' is preferable (that is, as a compound represented by the formula (I), a compound represented by the formula (I') is preferable).
  • benzene ring optionally further having substituent(s) or pyridine ring optionally further having substituent(s) is particularly preferable, and benzene ring optionally further having substituent(s) is particularly preferable.
  • the benzene ring and pyridine ring optionally further have, 1 to 3 (preferably 1 or 2) substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkyl, optionally halogenated C 1-4 alkoxy, amino, mono- and di-C 1-4 alkylamino and the like are preferable.
  • R 2 and the substituent on ring A (or ring A') other than R 3 are optionally bonded to each other to form an optionally substituted ring.
  • R 2 and the substituent on ring A (or ring A') other than R 3 are optionally bonded to each other to form an optionally substituted ring.
  • 5- to 8-membered (preferably 6- to 8-membered) heterocycle which contains one nitrogen atom, and further may contain 1 or 2 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom can be mentioned.
  • substituents that a ring optionally formed by R 2 and the substituent on ring A (or ring A') other than R 3 bonded to each other optionally has, groups similar to the substituents that the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R 1a or R 1b optionally has (preferably halogen atom, hydroxy, oxo, optionally halogenated C 1-4 alkyl, optionally halogenated C 1-6 alkoxy, carbamoyl, carboxyl, C 1-6 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino and the like) can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • R 1a and R 2 are optionally bonded to each other to form an optionally substituted ring.
  • ring optionally formed by R 1a and R 2 bonded to each other 5- to 8-membered (preferably 6- to 8-membered) heterocycle which contains one nitrogen atom, and further may contain 1 or 2 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom can be mentioned.
  • substituents that the ring formed by R 1a and R 2 bonded to each other optionally has, groups similar to the substituents that the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R 1a or R 1b optionally has (preferably halogen atom, hydroxy, oxo, optionally halogenated C 1-4 alkyl, optionally halogenated C 1-6 alkoxy, carbamoyl, carboxyl, C 1-6 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino and the like) can be mentioned, and 1 to 5 (preferably 1 to 3) of these optional substituents may be present at substitutable position(s).
  • R 4 when ring A' is a benzene ring optionally further having substituent(s), R 4 is not methyl, in other words, R 3 is not -NHCOCH 3 .
  • R 4 when ring A' is a benzene ring optionally further having substituent(s), R 4 is preferably substituted methyl, optionally substituted C 2-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted phenyl or optionally substituted C 3-7 cycloalkyl.
  • the methyl is substituted by 1 to 5 (preferably 1 to 3) substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, C 1-6 alkanoylamino, optionally halogenated C 1-6 alkoxy-carbonylamino, optionally halogenated C 1-4 alkylthio, optionally halogenated C 1-4 alkylsulfinyl, optionally halogenated C 1-4 alkylsulfonyl, thienyl and the like.
  • substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, C 1-6 alkanoylamino, optionally halogenated C 1-6 alkoxy-carbonylamin
  • the C 2-6 alkyl, C 2-6 alkenyl, phenyl and C 3-7 cycloalkyl are each optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from halogen atom, hydroxy, optionally halogenated C 1-4 alkoxy, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, C 1-6 alkanoylamino, optionally halogenated C 1-6 alkoxy-carbonylamino, optionally halogenated C 1-4 alkylthio, optionally halogenated C 1-4 alkylsulfinyl, optionally halogenated C 1-4 alkylsulfonyl, thienyl and the like.
  • ring A' is a benzene ring optionally further having substituent(s), as the R 4 , methyl substituted by 1 to 3 substituents selected from halogen atom, C 1-4 alkoxy, carboxyl, C 1-4 alkoxy-carbonyl, amino, mono- or di-C 1-4 alkylamino, C 1-6 alkanoylamino, C 1-6 alkoxy-carbonylamino and thienyl; C 2-6 alkyl optionally substituted by 1 to 3 substituents selected from halogen atom, carboxyl, C 1-4 alkylthio, C 1-4 alkylsulfinyl and C 1-4 alkylsulfonyl; C 2-6 alkenyl; phenyl optionally substituted by 1 to 3 substituents selected from halogen atom and C 1-4 alkoxy; or C 3-7 cycloalkyl is more preferable, and trifluoromethyl, 2,2,2-trifluoroe
  • a salt of a compound represented by the formula (I) (including a compound represented by the formula (I')), a pharmacologically acceptable salt and the like can be mentioned.
  • an acid addition salt with acid such as trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydriodic acid, sulfamic acid, sulfuric acid and the like; for example, a salt with a metal such as sodium, potassium, magnesium, calcium and the like; for example, a salt with organic base such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N
  • a prodrug of a compound represented by the formula (I) or a salt thereof means a compound which is converted to compound (I) with a reaction due to an enzyme, gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to compound (I) with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to compound (I) by hydrolysis etc. due to gastric acid, etc.
  • a prodrug of compound (I) may be a compound obtained by subjecting an amino group in compound (I) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in compound (I) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in compound (I) to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in compound (I) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethyla
  • a prodrug for compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990 ).
  • compound (I) has isomers such as optical isomer, stereoisomer, positional isomer, rotational isomer and the like, and any isomers and mixtures of the isomers are encompassed in the compound (I).
  • compound (I) has an optical isomer
  • an optical isomer separated from a racemate is also encompassed in the compound (I).
  • These isomers can be obtained as independent products by a synthesis means or a separation means (concentration, solvent extraction, column chromatography, recrystallization and the like) known per se.
  • the compound (I) may be a crystal or amorphous form.
  • compound (I) is a crystal, both a single crystal and a crystal mixture are both encompassed in compound (I).
  • Crystals can be produced by crystallization by applying a crystallization method known per se.
  • the compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in compound (I).
  • the compound (I) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I and the like) and the like.
  • an isotope e.g., 3 H, 14 C, 35 S, 125 I and the like
  • a compound represented by the formula (I) or a salt thereof can be produced by a method according to a method known per se (e.g., methods described in A.R. Katritzky et al., Heterocycles, 60, 1225, 2003 ; A. Da Settimo et al., II Farmaco-Ed. Sci., 38, 725, 1983 ; G. A. Romerio et al., Tetrahedron Letters, 38, 5103, 1997 and the like), for example, methods A - C shown below.
  • Each compound described in the following schemes may form a salt as long as it does not inhibit the reaction, and as such salt, those similar to the salt of compound (I) and the like can be mentioned.
  • R 1a , R 1b , R 2 , R 3 and ring A are as defined for R 1a , R 1b , R 2 , R 3 and ring A in compound (I), provided that R 2 and the substituent on ring A other than R 3 are not bonded to each other to form an optionally substituted ring, and R 1a and R 2 are not bonded to each other to form an optionally substituted ring.
  • R 1a , R 1b , R 2 , R 3 and ring A are as defined for R 1a , R 1b , R 2 , R 3 and ring A in compound (I), provided that R 2 and the substituent on ring A other than R 3 are not bonded to each other to form an optionally substituted ring.
  • R 1a , R 1b , R 2 , R 3 and ring A are as defined for R 1a , R 1b , R 2 , R 3 and ring A in compound (I).
  • Compound (I) or a salt thereof can be produced by reacting a compound (II) represented by the formula (II) wherein R 3 and ring A are as defined for R 3 and ring A in the aforementioned compound (I), or a salt thereof, with a compound (III) represented by the formula (III) wherein R 1a , R 1b and R 2 are as defined for R 1a , R 1b and R 2 in the aforementioned compound (I), provided that R 2 and the substituent on ring A other than R 3 are not bonded to each other to form an optionally substituted ring, and R 1a and R 2 are not bonded to each other to form an optionally substituted ring, or a salt thereof.
  • a salt of compound (II) or compound (III) those similar to the salt of compound (I) and the like can be mentioned.
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvent e.g., alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol etc.), ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether etc.), esters (e.g., ethyl formate, ethyl acetate, n-butyl acetate etc.), carboxylic acids (e.g., formic acid, acetic acid, propionic acid etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dich
  • the reaction temperature is -20°C to 200°C, and preferably 0°C to 170°C.
  • reaction time varies depending on the kind of compound (II) or (III), the kind of the solvent, reaction temperature and the like, it is generally about 1 min to about 2 weeks, preferably about 30 min to about 72 hr.
  • Compound (I) or a salt thereof can be produced by reacting a compound (II) represented by the formula (II) wherein R 3 and ring A are as defined for R 3 and ring A in compound (I), or a salt thereof with a compound (IV) represented by the formula (IV) wherein R 1a , R 1b and R 2 are as defined for R 1a , R 1b and R 2 in compound (I), provided that R 2 and the substituent on ring A other than R 3 are not bonded to each other to form an optionally substituted ring, or a salt thereof.
  • a salt of compound (II) or compound (IV) those similar to the salt of compound (I) and the like can be mentioned.
  • This reaction is generally performed in the presence of a base, and as such base, for example, metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like; inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal salts of C 1-6 lower fatty acid such as sodium formate, sodium acetate, potassium acetate and the like; tertiary amines such as triethylamine, tri(n-propyl)amine, tri(n-butyl)amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, ⁇ -collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like are used.
  • the amount of the base to be used is 1
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvent e.g., alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol etc.), ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether etc.), esters (e.g., ethyl formate, ethyl acetate, n-butyl acetate etc.), carboxylic acids (e.g., formic acid, acetic acid, propionic acid etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dich
  • the reaction temperature is -20°C to 200°C, preferably 0°C to 170°C.
  • reaction time varies depending on the kind of compound (II) or (IV), the kind of the solvent, reaction temperature and the like, it is generally about 1 min to about 1 week, preferably about 15 min to about 48 hr.
  • Compound (I) or a salt thereof can be produced by treating a compound (V) represented by the formula (V) wherein R 1a , R 1b , R 2 , R 3 and ring A are as defined for R 1a , R 1b , R 2 , R 3 and ring A in compound (I), or a salt thereof with a diazotizating reagent.
  • a salt of compound (V) those similar to the salt of compound (I) and the like can be mentioned.
  • the diazotizating reagent to be used for this reaction for example, arylsulfonyl azides such as benzenesulfonyl azide, p-toluenesulfonyl azide, p-dodecylbenzenesulfonyl azide and the like; alkylsulfonyl azides such as methanesulfonyl azide and the like; and the like are used.
  • the amount of the diazotizating reagent to be used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (V).
  • polymer-supported benzenesulfonyl azide e.g., polystyrene-supported benzenesulfonyl azide described in G. M. Green et al., 66, 2509, 2001 and the like
  • polystyrene-supported benzenesulfonyl azide described in G. M. Green et al., 66, 2509, 2001 and the like
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvent e.g., alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol etc.), ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether etc.), esters (e.g., ethyl formate, ethyl acetate, n-butyl acetate etc.), carboxylic acids (e.g., formic acid, acetic acid, propionic acid etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dich
  • this reaction may be performed in the presence of a base, and as such base, for example, metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like; metal hydrides such as sodium hydride, potassium hydride, calcium hydride and the like; inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal salts of C 1-6 lower fatty acid such as sodium formate, sodium acetate, potassium acetate and the like; tertiary amines such as triethylamine, tri(n-propyl)amine, tri(n-butyl)amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, ⁇ -collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrol
  • the reaction temperature is -20°C to 200°C, preferably 0°C to 170°C.
  • reaction time varies depending on the kind of compound (V), the kind of the solvent, reaction temperature and the like, it is generally about 1 min to about 1 week, preferably about 15 min to about 48 hr.
  • a ring formation reaction may be performed using a compound containing halogen atom (e.g., chlorine, bromine, iodine etc.), protected amino group, nitro group, C 1-6 lower alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl etc.) and the like instead of R 3 in compound (II) or (V), after which the halogen atom, protected amino group, nitro group, C 1-6 lower alkoxy-carbonyl group and the like may be converted to R 3 by a method known per se.
  • halogen atom e.g., chlorine, bromine, iodine etc.
  • protected amino group e.g., nitro group
  • C 1-6 lower alkoxy-carbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl etc.
  • a ring formation reaction may be performed using a compound containing cyano group, C 1-6 lower alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl etc.) and the like instead of CONR 1a R 1b of compound (III), compound (IV) or compound (V), after which the cyano group, C 1-6 lower alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl etc.) and the like may be converted to CONR 1a R 1b by a method known per se.
  • a compound containing cyano group, C 1-6 lower alkoxy-carbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl etc.
  • R 1a , R 1b , R 2 , R 3 and ring A has a substituent
  • the substituent can be introduced before or after the ring formation reaction shown in methods A - C by a reaction according to the kind of the substituent.
  • the substituent is preferably protected as necessary and, as the protecting group, those known per se can be used.
  • a compound represented by the formula (I') or a salt thereof (hereinafter sometimes referred to as compound (I')) can be produced in the same manner as in the aforementioned methods A-C.
  • R 1a , R 1b , R 2 , R 3 and ring A' are as defined for R 1a , R 1b , R 2 , R 3 and ring A' in compound (I'), provided that R 2 and the substituent on ring A' other than R 3 are not bonded to each other to form an optionally substituted ring, and R 1a and R 2 are not bonded to each other to form an optionally substituted ring.
  • Compound (I') or a salt thereof can be produced by reacting compound (II') or a salt thereof with compound (III) or a salt thereof.
  • As a salt of compound (II') or compound (III), those similar to the salt of compound (I) and the like can be mentioned.
  • This reaction can be performed in the same manner as in method A.
  • R 1a , R 1b , R 2 , R 3 and ring A' are as defined for R 1a , R 1b , R 2 , R 3 and ring A' in compound (I'), provided that R 2 and the substituent on ring A' other than R 3 are not bonded to each other to form an optionally substituted ring.
  • Compound (I') or a salt thereof can be produced by reacting compound (II') or a salt thereof with compound (IV) or a salt thereof.
  • As a salt of compound (II') or compound (IV), those similar to the salt of compound (I) and the like can be mentioned.
  • This reaction can be performed in the same manner as in method B.
  • R 1a , R 1b , R 2 , R 3 and ring A' are as defined for R 1a , R 1b , R 2 , R 3 and ring A' in compound (I').
  • Compound (I') or a salt thereof can be produced by treating a compound (V') or a salt thereof with a diazotiating reagent.
  • a salt of compound (V') those similar to the salt of compound (I) and the like can be mentioned.
  • This reaction can be performed in the same manner as in method C.
  • the compound (I) of the present invention or a salt thereof is low toxic and safe (e.g., superior as a pharmaceutical agent from the aspects of acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity etc.), and is preferably used for the prophylaxis or treatment of various arterial and/or venous thromboses, for example, myocardial infarction, cerebral infarction, arteriosclerosis obliterans and the like, in an animal, particularly mammals (e.g., human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog, rabbit, etc.).
  • the compound (I) of the present invention or a salt thereof can be used, for example, for the prophylaxis or treatment of the following diseases and the like.
  • ischemic cerebrovascular disorder acute cerebral thrombosis, cerebrovascular contraction after subarachnoid hemorrhage, Alzheimer's disease, transient ischemic attack (TIA), mixed dementia, cerebrovascular dementia, asymptomatic/multiple cerebral infarction, lacunar infarction and the like, prognosis improvement or secondary onset prevention of cerebral infarction, prevention or treatment of thrombus after an extracranial-intracranial artery bypass surgery, combination use or supplemental use with a thrombolytic agent against cerebral infarction (among them, ischemic cerebrovascular disorder), combination therapy with warfarin, heparin, low-molecular-weight heparin, thrombin inhibitor, FXa inhibitor or the like in preventing onset of cerebral infarction.
  • TIA transient ischemic attack
  • mixed dementia cerebrovascular dementia
  • asymptomatic/multiple cerebral infarction lacunar infarction and the like
  • prognosis improvement or secondary onset prevention of cerebral infarction prevention
  • acute coronary artery disease such as acute coronary syndrome or acute myocardial infarction, myocardial infarction, ischemic coronary artery disease, unstable angina pectoris, cardiomyopathy, acute heart failure, congestive chronic heart failure, vascular reocclusion and restenosis after coronary artery intervention such as stent indwelling or PTCA (percutaneous transluminal coronary angioplasty) or atherectomy, prevention or treatment of vascular reocclusion and restenosis after coronary artery bypass surgery, combination use or supplemental use with a thrombolytic agent against acute coronary artery disease, combination therapy with warfarin, heparin, low-molecular-weight heparin, thrombin inhibitor, FXa inhibitor or the like in preventing onset of myocardial infarction.
  • acute coronary syndrome or acute myocardial infarction myocardial infarction
  • myocardial infarction ischemic coronary artery disease
  • unstable angina pectoris cardiomy
  • diabetic nephropathy chronic glumerular nephritis, IgA nephropathy etc.
  • diabetic circulatory disorder pain, neuropathy, diabetic complication such as diabetic retinopathy and the like, prevention or treatment of thrombus after peripheral vascular bypass surgery or artificial blood vessel or vena cava filter indwelling, prevention or treatment of reocclusion and restenosis after peripheral vascular intervention such as stent indwelling or PTA (percutaneous transluminal angioplasty) or atherectomy, combination therapy with warfarin, heparin, low-molecular-weight heparin, thrombin inhibitor, FXa inhibitor or the like in therapy of peripheral circulatory failure such as arteriosclerosis obliterans.
  • PTA percutaneous transluminal angioplasty
  • atherectomy combination therapy with warfarin, heparin, low-molecular-weight heparin, thrombin inhibitor, FXa inhibitor or the like in therapy of peripheral circulatory failure such
  • thrombocytopenic purpura disseminated intravascular coagulation syndrome (DIC) developed in a patient suffering from progression of arteriosclerosis or cancer metastasis or systemic inflammatory reaction syndrome (SIRS) or pancreatitis or cancer or leukemia or a major surgery or sepsis or the like
  • various organ disorders such as liver function disorder caused by oligemia or ischemia or retention of blood, various organ failures (e.g.
  • lung failure liver failure, renal failure, heart failure etc.
  • DIC systemic lupus erythematosus
  • collagen disease hyperthyroidism
  • parturient paralysis and the like
  • inhibition of rejection reaction on transplantation organ protection or function improvement on transplantation, promotion of healing of bedsore or wound, and the like.
  • thrombin receptors particularly PAR-1
  • anticoagulants such as heparin, warfarin, FXa inhibitor and the like, namely, pharmaceutical agents inhibiting thrombin production, inhibit not only PAR-1-mediated platelet activation but also the blood coagulation system, frequently causing a serious hemorrhagic side effect.
  • the thrombin receptor antagonist of the present invention does not directly influence the blood coagulation system and can suppress activation of platelet by thrombin, it is promising as an antithrombotic agent.
  • the pharmaceutical agent can inhibit thrombin receptors (particularly PAR-1) expressed in various tissues, it can effectively act in a thrombin receptor mediated pathological condition or disease other than thrombosis without directly influencing the blood coagulation system.
  • the compound (I) in the pharmaceutical agent of the present invention, can be administered orally or parenterally as it is or after mixing with a pharmacologically acceptable carrier.
  • the dosage form of a pharmaceutical agent containing compound (I) of the present invention when used for oral administration include tablet (including sugar-coated tablet, film-coated tablet), pill, granule, powder, capsule (including soft capsule, microcapsule), syrup, emulsion, suspension and the like, and the dosage form thereof for parenteral administration is, for example, injection, injecting agent, instillation, suppository and the like.
  • a sustained release preparation by combining with a suitable base (e.g., polymer of butyric acid, polymer of glycolic acid, copolymer of butyric acid-glycolic acid, a mixture of polymer of butyric acid and polymer of glycolic acid, polyglycerol fatty acid ester etc.).
  • a suitable base e.g., polymer of butyric acid, polymer of glycolic acid, copolymer of butyric acid-glycolic acid, a mixture of polymer of butyric acid and polymer of glycolic acid, polyglycerol fatty acid ester etc.
  • the content of the compound (I) in the preparation of the present invention varies depending on the form of a preparation, and is usually from 2 to 85 wt%, preferably from 5 to 70 wt%, based on the whole preparation.
  • a known production method generally used in the pertinent field can be applied.
  • suitable amounts of additives such as an excipients, a binder, a disintegrant, a lubricant, a sweetener, a surfactant, a suspending agent, an emulsifier and the like generally used in the pertinent field are appropriately added as necessary, and produced.
  • the compound (I) When the compound (I) is prepared into a tablet, for example, it can be produced by adding an excipient, a binder, a disintegrant, a lubricant and the like, and when a pill and a granule are to be prepared, they can be produced by adding an excipient, a binder, a disintegrant and the like.
  • a powder and a capsule When a powder and a capsule are to be prepared, they can be produced by adding an excipient and the like, and when a syrup is to be prepared, it can be produced by adding a sweetener and the like, and when an emulsion or a suspension is to be prepared, it can be produced by adding a suspending agent, a surfactant, an emulsifier and the like.
  • excipient examples include lactose, sucrose, glucose, starch, saccharose, microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like.
  • binder examples include 5 - 10 wt% starch liquid paste, 10 - 20 wt% gum arabic solution or gelatin solution, 1 - 5 wt% tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
  • disintegrant examples include starch, calcium carbonate and the like.
  • lubricant examples include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
  • sweetener examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
  • suspending agent examples include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
  • emulsifier examples include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
  • a suitable amount of a colorant, a preservative, an aromatic, a corrigent, a stabilizer, a thickening agent and the like typically used in the field of preparation can be added on demand.
  • the pharmaceutical agent of the present invention is stable and low toxic, and can be used safely. While the daily dose varies depending on the condition and body weight of patients, the kind of compound, administration route and the like, in the case of, for example, oral administration to patients of thrombosis, the daily dose to an adult (body weight about 60 kg) is about 1 to 2000 mg, preferably about 3 to 1000 mg, more preferably about 10 to 500 mg, as an active ingredient (the compound (I)), which can be given in a single administration or administered in 2 or 3 portions a day.
  • the compound (I) When the compound (I) is administered parenterally, it is generally administered in the form of a liquid formulation (e.g., injection). While the dose varies depending on the subject of administration, target organ, symptom, administration method and the like, it is, for example, about 0.01 mg to about 100 mg, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, in the form of an injection, relative to 1 kg of body weight, which is preferably given by intravenous injection. As the injection, intravenous injection as well as subcutaneous injection, intracutaneous injection, intramuscular injection, instillation and the like are mentioned, and as a sustained release preparation, iontophoresis transdermal agent and the like are mentioned.
  • a liquid formulation e.g., injection
  • the dose varies depending on the subject of administration, target organ, symptom, administration method and the like, it is, for example, about 0.01 mg to about 100 mg, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg,
  • Such injections are prepared by methods known per se, or by dissolving, suspending or emulsifying the compound (I) in a sterilized aqueous solution or oily liquid.
  • aqueous solution for injection physiological saline, isotonic solutions containing glucose or other auxiliary drugs (e.g., D-sorbitol, D-mannitol, sodium chloride and the like) and the like can be mentioned, and they can be used in combination with suitable solubilizing agents, such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50) and the like.
  • alcohols e.g., ethanol
  • polyalcohols e.g., propylene glycol, polyethylene glycol
  • nonionic surfactants e.g., polysorbate 80, HCO-50
  • sesame oil, soybean oil and the like can be mentioned, which may be used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol and the like.
  • buffers e.g., phosphate buffer, sodium acetate buffer
  • soothing agents e.g., benzalkonium chloride, procaine hydrochloride and the like
  • stabilizers e.g., human serum albumin, polyethylene glycol and the like
  • preservatives e.g., benzyl alcohol, phenol and the like
  • a prepared injection is generally filled in an ampoule.
  • the compound (I) can be used in combination with suitable pharmaceutical agents (hereinafter abbreviated as concomitant drugs) such as thrombolytic agent (e.g., TPA, urokinase etc.), therapeutic agent for Alzheimer's disease (for example, Avan, Calan etc.), therapeutic agent for hyperlipidemia (e.g., HMG-CoA reductase inhibitor such as simvastatin, pravastatin etc.; nicotinic acid preparation such as nicomol etc.; cholesterol absorption inhibitor such as ezetimibe etc.; squalene synthase inhibitor and the like), TG lowering agent (e.g., clofibrate etc.), AII antagonist (e.g., candesartan cilexetil, losartan, telmisartan, olmesartan medoxomil etc.), antiplatelet agent (e.g., clopidogrel, aspirin, cilostazol etc.), Ca
  • the concomitant drug may be a low-molecular-weight compound or a high-molecular-weight protein, polypeptide, antibody or vaccine etc.
  • the administration mode of the compound of the present invention and the concomitant drug is not particularly restricted, and it is sufficient that the compound of the present invention and the concomitant drug are combined in administration. Examples of such administration mode include the following methods:
  • the elution in column chromatography of Examples was carried out under observation by means of TLC (Thin Layer Chromatography).
  • TLC Thin Layer Chromatography
  • 60F 254 manufactured by Merck & Co., Inc.
  • NH manufactured by Fuji Silysia Chemical, Ltd.
  • the solvent used for the elution in column chromatography was adopted as an eluent
  • a UV detector was adopted as the means for detection.
  • silica gel for column Kieselgel 60 (70 to 230 meshes) or Kieselgel 60 (230 to 400 meshes) manufactured by Merck & Co., Inc. was used.
  • NH-DM 1020 manufactured by Fuji Silysia Chemical, Ltd.; 100 to 200 mesh
  • NMR spectra were measured with a Varian Gemini 200 or Mercury 300 spectrometer by using tetramethylsilane as internal or external standard. The chemical shift was indicated by ⁇ , and a coupling constant was indicated by Hz.
  • IR spectra were measured with a Shimadzu FTZR-8200 spectrometer.
  • the numeric value in parenthesis with regard to a mixed solvent is a volumetric mixing ratio of each solvent. Moreover, "%" in the solution represents the number of grams in 100 ml of a solution. Abbreviations employed in Examples are described below.
  • Example 3 In the same manner as in Example 3, the title compound was obtained as a white powder (0.4 g, 81%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.4 g) obtained in Example 1d) and butanoyl chloride (0.15 ml).
  • Example 3 In the same manner as in Example 3, the title compound was obtained as a white powder (0.46 g, 79%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.4 g) obtained in Example 1d) and 4-methoxybenzoyl chloride (0.21 ml).
  • Example 3 In the same manner as in Example 3, the title compound was obtained as a white powder (0.46 g, 81%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.40 g) obtained in Example 1d) and 4-fluorobenzoyl chloride (0.18 ml).
  • Example 3 In the same manner as in Example 3, the title compound was obtained as a white powder (0.42 g, 70%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.40 g) obtained in Example 1d) and 4-chlorobenzoyl chloride (0.19 ml).
  • Example 3 In the same manner as in Example 3, the title compound was obtained as white needle crystals (0.42 g, 97%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) and 4-bromobutyryl chloride (0.12 ml).
  • Example 3 In the same manner as in Example 3, the title compound was obtained as a white powder (0.62 g, 80%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.57 g) obtained in Example 1d) and 3-(methylthio)propanoyl chloride (0.24 ml).
  • Example 1e the title compound was obtained as a colorless powder (0.25 g, 21%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (1.00 g) obtained in Example 1d) and 3-chloropropionyl chloride (0.41 ml).
  • Example 1e the title compound was obtained as a colorless powder (2.70 g, 96%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (2.00 g) obtained in Example 1d) and ethyl 3-chloro-3-oxopropanoate (1.10 ml).
  • Example 19 the title compound was obtained as a pale-yellow powder (0.08 g, 32%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.17 g) obtained in Example 1d) and 2-thienylacetic acid (0.10 mg).
  • Example 19 the title compound was obtained as a pale-yellow powder (0.06 g, 24%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.17 g) obtained in Example 1d) and 3-thienylacetic acid (0.10 mg).
  • Example 19 the title compound was obtained as a white powder (0.83 g, 58%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.91 g) obtained in Example 1d) and N-(tert-butoxycarbonyl)glycine (0.67 g).
  • Example 3 In the same manner as in Example 3, the title compound was obtained as a white powder (0.12 g, 79%) from N-cyclopropyl-1-[4-(glycylamino)phenyl]-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.15 g) obtained in Example 23a) and acetyl chloride (0.03 ml).
  • Example 19 the title compound was obtained as a white powder (0.08 g, 31%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.20 g) obtained in Example 1d) and ethoxyacetic acid (0.08 ml).
  • Example 19 In the same manner as in Example 19, the title compound was obtained as a white powder (0.12 g, 43%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.20 g) obtained in Example 1d) and 3,3,3-trifluoropropanoic acid (0.07 ml).
  • Example 26a N-(5-nitropyridin-2-yl)acetamide (2.4 g) obtained in Example 26a).
  • Example 26b N-(5-aminopyridin-2-yl)acetamide (0.91 g) obtained in Example 26b).
  • Example 26d To a solution of methyl 1-[6-(acetylamino)pyridin-3-yl]-5-propyl-1H-1,2,3-triazole-4-carboxylate (0.55 g) obtained in Example 26d) in ethanol (5 ml) was added 8N aqueous sodium hydroxide solution (0.45 ml), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, toluene (5 ml) was added to the residue. The solvent was evaporated under reduced pressure.
  • Example 28 In the same manner as in Example 28, the title compound was obtained as a colorless powder (0.14 g, 54%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.20 g) obtained in Example 1d).
  • Example 1d the title compound was obtained as a colorless powder (0.06 g, 20%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.21 g) obtained in Example 1d).
  • Example 28 In the same manner as in Example 28, the title compound was obtained as a colorless powder (0.10 g, 34%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.24 g) obtained in Example 1d).
  • Example 28 In the same manner as in Example 28, the title compound was obtained as a colorless powder (0.10 g, 23%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.32 g) obtained in Example 1d).
  • Example 1d the title compound was obtained as a colorless powder (0.28 g, 44%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.50 g) obtained in Example 1d).
  • Example 28 In the same manner as in Example 28, the title compound was obtained as a colorless powder (0.58 g, 90%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.45 g) obtained in Example 1d).
  • Example 35 In the same manner as in Example 35, the title compound was obtained as a colorless powder (0.39 g, 88%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.32 g) obtained in Example 1d).
  • Example 35 In the same manner as in Example 35, the title compound was obtained as a colorless powder (0.29 g, 88%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.34 g) obtained in Example 1d).
  • Example 35 In the same manner as in Example 35, the title compound was obtained as a colorless powder (0.12 g, 24%) from 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.38 g) obtained in Example 1d).
  • Example 43b the title compound was obtained as a white powder (1.3 g, 79%) from 4-azido-N-methylbenzamide (1.0 g) obtained in Example 44a) and ethyl 3-keto-n-hexanoate (1.1 ml).
  • Example 43c the title compound was obtained as a white powder (0.28 g, 84%) from 1- ⁇ 4-[(methylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.29 g) obtained in Example 44b) and cyclopropylamine (0.08 ml).
  • Example 43b the title compound was obtained as a white powder (3.6 g, 64%) from 4-azido-N-(2-hydroxyethyl)benzamide (3.6 g) obtained in Example 45a) and ethyl 3-keto-n-hexanoate (3.4 ml).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as white needle crystals (0.13 g, 46%) from 1-(4- ⁇ [(2-hydroxyethyl)amino]carbonyl ⁇ phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.26 g) obtained in Example 45b) and cyclopropylamine (0.07 ml).
  • Example 43c the title compound was obtained as pale-yellow plate crystals (0.52 g, 69%) from 5-propyl-1-(4- ⁇ [(2,2,2-trifluoroethyl)amino]carbonyl ⁇ phenyl)-1H-1,2,3-triazole-4-carboxylic acid (0.67 g) obtained in Example 46b) and cyclopropylamine (0.16 ml).
  • Example 43b the title compound was obtained as a pale-yellow solid (1.3 g, 92%) from 4-azido-N-(2-furylmethyl)benzamide (0.97 g) obtained in Example 47a) and ethyl 3-keto-n-hexanoate (0.77 ml).
  • Example 43c the title compound was obtained as colorless needle crystals (0.54 g, 72%) from 1-(4- ⁇ [(2-furylmethyl)amino]carbonyl ⁇ phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.66 g) obtained in Example 47b) and cyclopropylamine (0.16 ml).
  • Example 43b the title compound was obtained as a white powder (1.1 g, 84%) from 4-azido-N-(2-methoxyethyl)benzamide (0.88 g) obtained in Example 48a) and ethyl 3-keto-n-hexanoate (0.77 ml).
  • Example 43c the title compound was obtained as a white solid (0.46 g, 84%) from 1-(4- ⁇ [(2-methoxyethyl)amino]carbonyl ⁇ phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.50 g) obtained in Example 48b) and cyclopropylamine (0.12 ml).
  • Example 43b In the same manner as in Example 43b), the title compound was obtained as a crude product (0.91 g, 63%) of yellow powder from 4-azido-N-isopropylbenzamide (0.93 g) obtained in Example 49a) and ethyl 3-keto-n-hexanoate (0.87 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as colorless plate crystals (0.80 g, 77%) from 1- ⁇ 4-[(isopropylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.91 g) obtained in Example 49b) and cyclopropylamine (0.08 ml).
  • Example 43b the title compound was obtained as a yellow powder (0.89 g, 64%) from 4-azido-N-(sec-butyl)benzamide (0.91 g) obtained in Example 50a) and ethyl 3-keto-n-hexanoate (0.80 ml).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a white powder (0.73 g, 74%) from 1- ⁇ 4-[(sec-butylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.89 g) obtained in Example 50b) and cyclopropylamine (0.22 ml).
  • Example 43b the title compound was obtained as a yellow powder (1.42 g, 100%) from 4-azido-N-(tert-butyl)benzamide (0.94 g) obtained in Example 51a) and ethyl 3-keto-n-hexanoate (0.83 ml).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as colorless plate crystals (1.17 g, 74%) from 1- ⁇ 4-[(tert-butylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (1.42 g) obtained in Example 51b) and cyclopropylamine (0.36 ml).
  • Example 43a In the same manner as in Example 43a), the title compound was obtained as a pale-yellow powder (0.85 g, 78%) from 4-azidobenzoic acid (0.82 g) and 2-methylpropan-1-amine (0.60 ml).
  • Example 43b the title compound was obtained as a yellow powder (1.29 g, 100%) from 4-azido-N-isobutylbenzamide (0.85 g) obtained in Example 52a) and ethyl 3-keto-n-hexanoate (0.75 ml).
  • Example 43c the title compound was obtained as colorless needle crystals (1.10 g, 76%) from 1- ⁇ 4-[(isobutylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (1.29 g) obtained in Example 52b) and cyclopropylamine (0.32 ml).
  • Example 43a In the same manner as in Example 43a), the title compound was obtained as a brown powder (1.44 g) from 4-azidobenzoic acid (1.00 g) and cyclopropylamine (0.85 ml).
  • Example 43b the title compound was obtained as a brown powder (1.53 g, 79%) from 4-azido-N-cyclopropylbenzamide (1.44 g) obtained in Example 53a).
  • Example 43c the title compound was obtained as a colorless powder (0.84 g, 81%) from 1- ⁇ 4-[(cyclopropylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.92 g) obtained in Example 53b).
  • Example 43a In the same manner as in Example 43a), the title compound was obtained as a pale-brown powder (1.75 g) from 4-azidobenzoic acid (1.00 g) and cyclopentylamine (1.21 ml).
  • Example 43b the title compound was obtained as a pale-brown powder (1.84 g, 88%) from 4-azido-N-cyclopentylbenzamide (1.75 g) obtained in Example 54a).
  • Example 43c the title compound was obtained as a colorless powder (0.26 g, 23%) from 1- ⁇ 4-[(cyclopentylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (1.00 g) obtained in Example 54b).
  • the organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml).
  • the aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0°C.
  • the precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.58 g, 4.99 mmol, 96.0%).
  • the reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine.
  • the aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml).
  • the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added.
  • the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (542 mg, 1.52 mmol, 97.1%).
  • reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30°C or below to give the title compound as a pale-yellow solid (2.3 g, including residual solvent).
  • the organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml).
  • the aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0°C.
  • the precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.62 g, 4.91 mmol, 97.1%).
  • the reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine.
  • the aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml).
  • the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added.
  • the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (535 mg, 1.45 mmol, 94.9%).
  • reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30°C or below to give the title compound as a pale-yellow solid (1.5 g, including residual solvent).
  • the organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml).
  • the aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0°C.
  • the precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.71 g, 4.97 mmol, 97.7%).
  • the reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine.
  • the aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml).
  • the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a white powder. This was crystallized from methanol-ethyl acetate to give the title compound as a white powder (298 mg, 0.777 mmol, 55.1%).
  • reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30°C or below to give the title compound as a pale-yellow solid.
  • the organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml).
  • the aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0°C.
  • the precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.71 g, 4.70 mmol, 91.3%).
  • the reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine.
  • the aqueous layers were each extracted with ethyl acetate-hexane (1:1, 30 ml).
  • the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added.
  • the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (520 mg, 1.29 mmol, 92.7%).
  • reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30°C or below to give the title compound as a pale-yellow solid.
  • the organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml).
  • the aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0°C.
  • the precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.86 g, 4.92 mmol, 97.1%).
  • reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30°C or below to give the title compound as a pale-yellow solid.
  • the reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (505 mg, 1.17 mmol, 90.7%).
  • Example 61b Sodium 1-(4- ⁇ [(2-morpholin-4-ylethyl)amino]carbonyl ⁇ phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylate (642 mg, 1.34 mmol) obtained in Example 61b), HOBt (91.6 mg, 0.671 mmol, 0.5 eq.) and cyclopropylamine (0.125 ml, 1.74 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (315 mg, 1.61 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 12 hr.
  • the reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate and diethyl ether were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (397 mg, 0.932 mmol, 69.6%).
  • the aqueous layer was neutralized (pH 6-7) with 6N hydrochloric acid and concentrated.
  • the residue was dissolved in isobutanol, THF and ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate and THF were added to the residue.
  • the precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound as a pale-brown powder (purity 90%, 2.05 g, 4.78 mmol, 92.9%).
  • reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed sequentially with 2% aqueous sodium carbonate solution-saturated brine (1:1, 40 ml x 2, 1:4, 40 ml x 1).
  • the aqueous layers were each extracted with ethyl acetate (30 ml).
  • the organic layers were combined and dried over anhydrous sodium sulfate and concentrated, the residue was dissolved in toluene, and the solution was subjected to column chromatography on NH silica gel (Fuji Silysia Chemical Ltd., 100-200 mesh, DM1020, 6 g).
  • the reaction mixture was diluted with ethyl acetate (70 ml) and hexane (30 ml) and washed with 2% aqueous sodium carbonate solution, saturated aqueous sodium hydrogen carbonate solution, 10% aqueous sodium chloride solution and saturated brine.
  • the aqueous layers were each extracted with ethyl acetate-hexane (2:1, 75 ml).
  • the organic layers were combined, dried over anhydrous sodium sulfate and concentrated at 30°C or below to give the title compound as a pale-brown solid (2.0 g).
  • the reaction mixture was concentrated, the residue was dissolved in ethyl acetate (40 ml), and the mixture was washed sequentially with 2% aqueous sodium carbonate solution-saturated brine (1:1, 40 ml x 2, 1:4, 40 ml x 1).
  • the aqueous layers were each extracted with ethyl acetate (30 ml).
  • the organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate and diethyl ether were added.
  • Example 1a 4-azidobenzonitrile was obtained as a crude product (3.99 g) from 4-aminobenzonitrile (3.54 g), sodium nitrite (2.10 g) and sodium azide (1.95 g). Then, in the same manner as in Example 1b), the title compound was obtained as a pale-yellow powder (1.56 g, 20%) from 4-azidobenzonitrile (3.99 g) and ethyl 3-keto-n-hexanoate (5.8 ml).
  • Example 1c the title compound was obtained as a pale-yellow oil (0.11 g, 36%) from 1-(4-cyanophenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.26 g) obtained in Example 64a) and cyclopropylamine (0.08 ml).
  • Example 65a In the same manner as in Example 1a), the title compound was obtained as a pale-brown powder (0.27 g, 65%) from 4-amino-N,2-dimethylbenzamide (0.40 g) obtained in Example 65a).
  • Example 43b In the same manner as in Example 43b), the title compound was obtained as a white powder (0.32 g, 75%) from 4-azido-N,2-dimethylbenzamide (0.27 g) obtained in Example 65b).
  • Example 65c the title compound was obtained as a colorless powder (0.24 g, 67%) from 1- ⁇ 3-methyl-4-[(methylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.32 g) obtained in Example 65c).
  • Example 66b the title compound was obtained as a pale-brown powder (1.22 g, 70%) from 4-amino-2-chloro-N-ethylbenzamide (1.55 g) obtained in Example 66b).
  • Example 43b the title compound was obtained as a white powder (1.67 g, 91%) from 4-azido-2-chloro-N-ethylbenzamide (1.22 g) obtained in Example 66c).
  • Example 43c the title compound was obtained as a colorless powder (0.42 g, 37%) from 1- ⁇ 3-chloro-4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (1.00 g) obtained in Example 66d).
  • Example 67a N-ethyl-2-fluoro-4-nitrobenzamide (0.85 g) obtained in Example 67a).
  • Example 67b the title compound was obtained as an orange powder (0.74 g, 89%) from 4-amino-N-ethyl-2-fluorobenzamide (0.81 g) obtained in Example 67b).
  • Example 43b In the same manner as in Example 43b), a mixture of the title compounds (about 6:4 mixture) was obtained as a brown oil (1.29 g) from 4-azido-N-ethyl-2-fluorobenzamide (0.74 g) obtained in Example 67c).
  • N-cyclopropyl-1- ⁇ 4-[(ethylamino)carbonyl]-3-fluorophenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxamide pale-yellow powder, 0.33 g, 31%)
  • N-cyclopropyl-1- ⁇ 3-ethoxy-4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxamide (white powder, 0.14 g, 9%) were obtained from a mixture (1.29 g) of 1- ⁇ 4-[(ethylamino)carbonyl]-3-fluorophenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid and 1- ⁇ 3-ethoxy-4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid
  • Example 68a N-ethyl-2-methyl-4-nitrobenzamide (0.92 g) obtained in Example 68a).
  • Example 68b In the same manner as in Example 1a), the title compound was obtained as an orange powder (0.81 g, 90%) from 4-amino-N-ethyl-2-methylbenzamide (0.95 g) obtained in Example 68b).
  • Example 43b the title compound was obtained as a white powder (1.01 g, 80%) from 4-azido-N-ethyl-2-methylbenzamide (0.81 g) obtained in Example 68c).
  • Example 43c the title compound was obtained as a colorless powder (0.43 g, 82%) from 1- ⁇ 4-[(ethylamino)carbonyl]-3-methylphenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 68d).
  • Example 69a the title compound was obtained as a yellow powder (0.87 g, 70%) from 4-amino-N-ethyl-2-methoxybenzamide (1.10 g) obtained in Example 69a).
  • Example 43b the title compound was obtained as a white powder (0.93 g, 71%) from 4-azido-N-ethyl-2-methoxybenzamide (0.87 g) obtained in Example 69b).
  • Example 69c the title compound was obtained as a colorless powder (0.29 g, 58%) from 1- ⁇ 4-[(ethylamino)carbonyl]-3-methoxyphenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 69c).
  • Example 1a the title compound was obtained as a yellow solid (1.7 g, 94%) from 4-amino-N-ethyl-3-methylbenzamide monohydrochloride (1.9 g) obtained in Example 70b), 1 M aqueous sodium nitrite solution (8.9 ml) and sodium azide (0.58 g).
  • Example 43b In the same manner as in Example 43b), the title compound was obtained as a red oil (0.58 g, 43%) from 4-azido-N-ethyl-3-methylbenzamide (0.85 g) obtained in Example 70c) and ethyl 3-keto-n-hexanoate (0.8 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a yellow amorphous solid (0.20 g, 31%) from 1- ⁇ 4-[(ethylamino)carbonyl]-2-methylphenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.58 g) obtained in Example 70d) and cyclopropylamine (0.15 ml).
  • Example 70b In the same manner as in Example 70b), the title compound was obtained as a white powder (6.5 g, 94%) from N-ethyl-3-methoxy-4-nitrobenzamide (6.7 g) obtained in Example 71a) and 10% Pd/C (50% wet, 0.67 g).
  • Example 1a the title compound was obtained as a brown solid (2.9 g, 94%) from 4-amino-N-ethyl-3-methoxybenzamide monohydrochloride (3.1 g) obtained in Example 71b), 1 M aqueous sodium nitrite solution (13 ml) and sodium azide (0.87 g).
  • Example 43b the title compound was obtained as a red oil (1.2 g, 59%) from 4-azido-N-ethyl-3-methoxybenzamide (1.4 g) obtained in Example 71c) and ethyl 3-keto-n-hexanoate (1.2 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a white powder (0.57 g, 42%) from 1- ⁇ 4-[(ethylamino)carbonyl]-2-methoxyphenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (1.2 g) obtained in Example 71d) and cyclopropylamine (0.31 ml).
  • Example 43a the title compound was obtained as a white solid (3.5 g, 100%) from 4-amino-3-chlorobenzoic acid (3.0 g) obtained in Example 72a) and 2M ethylamine in THF solution (11 ml).
  • Example 1a In the same manner as in Example 1a), the title compound was obtained as a brown solid (2.8 g, 69%) from 4-amino-3-chloro-N-ethylbenzamide (3.5 g) obtained in Example 72b), 1M aqueous sodium nitrite solution (21 ml) and sodium azide (1.4 g). The obtained crude product was used for the next reaction without further purification.
  • Example 43b the title compound was obtained as a red oil (0.91 g, 44%) from 4-azido-3-chloro-N-ethylbenzamide (1.4 g) obtained in Example 72c) and ethyl 3-keto-n-hexanoate (1.2 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a brown amorphous solid (0.08 g, 8%) from 1- ⁇ 2-chloro-4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.91 g) obtained in Example 72d) and cyclopropylamine (0.23 ml).
  • Example 43a In the same manner as in Example 43a), the title compound was obtained as a white powder (2.3 g, 100%) from 4-amino-5-chloro-2-methoxybenzoic acid (2.0 g) and 2M ethylamine in THF solution (6 ml).
  • NMR (CDCl 3 ) ⁇ : 1.22 (3H, t, J 6.8), 3.39-3.52 (2H, m), 3.89 (3H, s), 4.40 (2H, brs), 6.30 (1H, s), 7.63 (1H, brs), 8.11 (1H, s).
  • Example 1a In the same manner as in Example 1a), the title compound was obtained as a brown solid (2.0 g, 80%) from 4-amino-5-chloro-N-ethyl-2-methoxybenzamide (2.3 g) obtained in Example 73a), 1M aqueous sodium nitrite solution (10 ml) and sodium azide (0.65 g). The obtained crude product was used for the next reaction without further purification.
  • Example 43b In the same manner as in Example 43b), the title compound was obtained as a brown oil (0.46 g, 31%) from 4-azido-5-chloro-N-ethyl-2-methoxybenzamide (1.0 g) obtained in Example 73b) and ethyl 3-keto-n-hexanoate (0.77 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a white powder (0.02 g, 3%) from 1- ⁇ 2-chloro-4-[(ethylamino)carbonyl]-5-methoxyphenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.46 g) obtained in Example 73c) and cyclopropylamine (0.10 ml).
  • Example 1d the title compound was obtained as a colorless oil (0.53 g, 84%) from 3-ethoxy-N-ethyl-4-nitrobenzamide (0.72 g) obtained in Example 74b) and 10% Pd/C (50% wet, 0.07 g).
  • Example 1a In the same manner as in Example 1a), the title compound was obtained as a yellow oil (0.50 g, 85%) from 4-amino-3-ethoxy-N-ethylbenzamide (0.53 g) obtained in Example 74c), 1M aqueous sodium nitrite solution (2.5 ml) and sodium azide (0.17 g). The obtained crude product was used for the next reaction without further purification.
  • Example 43b In the same manner as in Example 43b), the title compound was obtained as a pale-brown solid (0.25 g, 73%) from 4-azido-3-ethoxy-N-ethylbenzamide (0.25 g) obtained in Example 74d) and ethyl 3-keto-n-hexanoate (0.19 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a pale-yellow powder (0.09 g, 31%) from 1- ⁇ 2-ethoxy-4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.25 g) obtained in Example 74e) and cyclopropylamine (0.06 ml).
  • Example 74b In the same manner as in Example 74b), the title compound was obtained as a yellow oil (0.47 g, 19%) from N-ethyl-3-hydroxy-4-nitrobenzamide (2.1 g) obtained in Example 74a), potassium carbonate (1.4 g) and 1-bromopropane (0.91 ml).
  • Example 1d the title compound was obtained as a colorless oil (0.29 g, 70%) from N-ethyl-4-nitro-3-propoxybenzamide (0.47 g) obtained in Example 75a) and 10% Pd/C (50% wet, 0.05 g).
  • Example 1a In the same manner as in Example 1a), the title compound was obtained as a yellow oil (0.33 g, 100%) from 4-amino-N-ethyl-3-propoxybenzamide (0.29 g) obtained in Example 75b), 1M aqueous sodium nitrite solution (1.3 ml) and sodium azide (0.09 g). The obtained crude product was used for the next reaction without further purification.
  • Example 43b In the same manner as in Example 43b), the title compound was obtained as a red oil (0.11 g, 46%) from 4-azido-N-ethyl-3-propoxybenzamide (0.16 g) obtained in Example 75c) and ethyl 3-keto-n-hexanoate (0.10 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a pale-yellow amorphous solid (0.07 g, 61%) from 1- ⁇ 4-[(ethylamino)carbonyl]-2-propoxyphenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.11 g) obtained in Example 75d) and cyclopropylamine (0.03 ml).
  • Example 43c the title compound was obtained as colorless needle crystals (0.22 g, 51%) from 1- ⁇ 2-chloro-4-[(ethylamino)carbonyl]-5-methoxyphenyl ⁇ -5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.38 g) obtained in Example 76a) and cyclopropylamine (0.09 ml).
  • Example 76a In the same manner as in Example 76a), the title compound was obtained as a red oil (0.43 g, 36%) from 4-azido-N-ethyl-3-methylbenzamide (0.85 g) obtained in Example 70c) and ethyl 3-keto-n-butanoate (0.64 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a white powder (0.23 g, 46%) from 1- ⁇ 4-[(ethylamino)carbonyl]-2-methylphenyl ⁇ -5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.43 g) obtained in Example 77a) and cyclopropylamine (0.13 ml).
  • Example 76a In the same manner as in Example 76a), the title compound was obtained as a red oil (0.85 g, 45%) from 4-azido-N-ethyl-3-methoxybenzamide (1.4 g) obtained in Example 71c) and ethyl 3-keto-n-butanoate (0.96 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a white powder (0.41 g, 43%) from 1- ⁇ 4-[(ethylamino)carbonyl]-2-methoxyphenyl ⁇ -5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.85 g) obtained in Example 78a) and cyclopropylamine (0.24 ml).
  • Example 76a In the same manner as in Example 76a), the title compound was obtained as a red oil (0.85 g, 45%) from 4-azido-3-chloro-N-ethylbenzamide (1.4 g) obtained in Example 72c) and ethyl 3-keto-n-butanoate (0.94 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a white powder (0.11 g, 12%) from 1- ⁇ 2-chloro-4-[(ethylamino)carbonyl]phenyl ⁇ -5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.85 g) obtained in Example 79a) and cyclopropylamine (0.23 ml).
  • Example 76a In the same manner as in Example 76a), the title compound was obtained as a pale-brown solid (0.19 g, 60%) from 4-azido-3-ethoxy-N-ethylbenzamide (0.25 g) obtained in Example 74d) and ethyl 3-keto-n-butanoate (0.15 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a white powder (0.13 g, 60%) from 1- ⁇ 2-ethoxy-4-[(ethylamino)carbonyl]phenyl ⁇ -5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.19 g) obtained in Example 80a) and cyclopropylamine (0.05 ml).
  • Example 76a In the same manner as in Example 76a), the title compound was obtained as a red oil (0.10 g, 46%) from 4-azido-N-ethyl-3-propoxybenzamide (0.16 g) obtained in Example 75c) and ethyl 3-keto-n-butanoate (0.10 ml). The obtained crude product was used for the next reaction without further purification.
  • Example 43c the title compound was obtained as a pale-yellow amorphous solid (0.09 g, 81%) from 1- ⁇ 4-[(ethylamino)carbonyl]-2-propoxyphenyl ⁇ -5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.10 g) obtained in Example 81a) and cyclopropylamine (0.03 ml).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.36 g, 47%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 1-(tetrahydrofuran-2-yl)methanamine (0.30 g).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.59 g, 73%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 1-(5-methylpyrazin-2-yl)methanamine (0.37 g).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.40 g, 51%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 1-(pyridin-2-yl)methanamine (0.32 g).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.44 g, 49%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 2,3,4,9-tetrahydro-1H- ⁇ -carboline (0.51 g).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.61 g, 71%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 1-(1,3-benzodioxol-5-yl)methanamine (0.45 g).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.50 g, 53%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.57 g).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.43 g, 53%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 3-fluorobenzylamine (0.37 g).
  • Example 43c In the same manner as in Example 43c), the title compound was obtained as a colorless powder (0.70 g, 82%) from 1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.60 g) obtained in Example 43b) and 1,2,3,4-tetrahydronaphthalen-1-amine (0.44 g).
  • Example 90a In the same manner as in Example 1c), the title compound was obtained as colorless plate crystals (1.53 g, 83%) from 5-butyl-1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -1H-1,2,3-triazole-4-carboxylic acid (1.66 g) obtained in Example 90a).
  • reaction mixture was stirred at room temperature for 11 hr, washed with 0.5M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated.
  • a solution of the residue in methanol (500 ml) was stirred with heating under reflux for 9 hr. After cooling to room temperature, the solvent was evaporated.
  • Example 90a In the same manner as in Example 90a), the title compound was obtained as a brown powder (2.20 g, 99%) from methyl 6-(benzyloxy)-3-oxohexanoate (1.00 g) obtained in Example 91a).
  • Example 91b the title compound was obtained as colorless needle crystals (1.74 g, 76%) from 5-[3-(benzyloxy)propyl]-1- ⁇ 4-[(ethylamino)carbonyl]phenyl ⁇ -1H-1,2,3-triazole-4-carboxylic acid (2.10 g) obtained in Example 91b).
  • the aqueous layer was acidified (pH ⁇ 3) with 6N hydrochloric acid and stood still at 0°C.
  • the precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-brown powder (1.33 g, 4.39 mmol, 93.4%).
  • the reaction mixture was concentrated, the residue was diluted with ethyl acetate-hexane (2:1, 45 ml), and the mixture was washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine.
  • the aqueous layers were each extracted with ethyl acetate-hexane (3:2, 30 ml).
  • the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added to the residue.
  • the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (476 mg, 1.39 mmol, 91.4%).
  • This oil was dissolved in ethanol (100 ml), and the mixture was stirred at 80°C for 2.5 hr under a nitrogen atmosphere.
  • the reaction mixture was concentrated, and the residue was diluted with ethyl acetate-hexane (2:1, 100 ml) and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • the aqueous layers were each extracted with ethyl acetate-hexane (2:1, 60 ml), and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated.

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009156082A1 (en) * 2008-06-28 2009-12-30 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones for the treatment of chronic obstructive pulmonary disease (copd) and/or asthma
DE102014108210A1 (de) 2014-06-11 2015-12-17 Dietrich Gulba Rodentizid
WO2019038405A1 (en) * 2017-08-23 2019-02-28 Helmholtz-Zentrum für Infektionsforschung GmbH NEW CYSTOBACTAMIDE DERIVATIVES
US10519099B2 (en) 2014-11-26 2019-12-31 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
US10793600B2 (en) 2013-07-12 2020-10-06 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
EP4070658A1 (de) 2021-04-06 2022-10-12 BIORoxx GmbH Verwendung von blutgerinnungshemmenden verbindungen als rodentizide
US12084452B2 (en) 2012-04-26 2024-09-10 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GEP20104994B (en) 2005-02-25 2010-05-25 Serenex Inc Tetrahydroindolone and tetrahydroindazolone derivatives
WO2008128038A2 (en) * 2007-04-13 2008-10-23 The Scripps Research Institute Methods and compositions for treating cardiac dysfunctions
US20110065725A1 (en) * 2008-03-18 2011-03-17 Glaxo Group Limited Triazole amide derivatives for use in therapy
CN102918034B (zh) 2010-03-30 2015-06-03 维颂公司 多取代芳族化合物作为凝血酶的抑制剂
DK2655345T3 (en) 2010-12-20 2015-05-04 Sigma Tau Res Switzerland Sa Aryltriazole Compounds with Anti-tumor Effect
LT2968297T (lt) 2013-03-15 2019-01-10 Verseon Corporation Multipakeistieji aromatiniai junginiai kaip serino proteazės inhibitoriai
ES2791749T3 (es) 2013-03-15 2020-11-05 Verseon Corp Halogenopirazoles como inhibidores de la trombina
US9238034B2 (en) * 2013-07-09 2016-01-19 The Translational Genomics Research Institute FN14 antagonists and therapeutic uses thereof
NO2721710T3 (de) 2014-08-21 2018-03-31
CN106687445A (zh) 2014-09-17 2017-05-17 维颂公司 作为丝氨酸蛋白酶抑制剂的吡唑基取代的吡啶酮化合物
RU2017131562A (ru) 2015-02-27 2019-03-27 Версеон Корпорейшн Замещенные пиразольные соединения как ингибиторы сериновых протеаз
JP7334979B2 (ja) * 2017-09-12 2023-08-29 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ イソプレニルシステインカルボキシルメチルトランスフェラーゼ阻害剤として有用な化合物
CN114656414B (zh) * 2022-05-24 2022-08-23 常熟华虞环境科技有限公司 三氮唑改性二氧化钛光催化剂及其制备方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5523310A (en) * 1994-12-05 1996-06-04 Hoffmann-La Roche Inc. 1,2,3-triazole derivatives
AU730224B2 (en) 1996-12-23 2001-03-01 Du Pont Pharmaceuticals Company Nitrogen containing heteroaromatics as factor Xa inhibitors
EP1042299A1 (de) 1997-12-22 2000-10-11 Du Pont Pharmaceuticals Company Stickstoffenthaltende heteroaromaten mit ortho-substituierten p1 gruppen als faktor-xa-inhibitoren
US6365617B1 (en) 1999-06-29 2002-04-02 Ortho-Mcneil Pharmaceutical, Inc. Indole and indazole urea-peptoids as thrombin receptor antagonists
US6858577B1 (en) 1999-06-29 2005-02-22 Ortho-Mcneil Pharmaceutical, Inc. Indole peptidomimetics as thrombin receptor antagonists
NZ528820A (en) 2001-04-19 2007-01-26 Eisai Co Ltd 2-iminopyrrolidine derivatives
ATE329909T1 (de) * 2002-11-27 2006-07-15 Boehringer Ingelheim Pharma 1,2,3-triazolamid-derivate als cytokininhibitoren
DE10315570A1 (de) 2003-04-05 2004-10-14 Merck Patent Gmbh Triazolderivate
ATE501128T1 (de) * 2003-12-03 2011-03-15 Boehringer Ingelheim Pharma 1,2,3-triazolamidderivate als inhibitoren der cytokinproduktion

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO2006109846A1 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009156082A1 (en) * 2008-06-28 2009-12-30 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones for the treatment of chronic obstructive pulmonary disease (copd) and/or asthma
EP2138178A1 (de) * 2008-06-28 2009-12-30 Bayer Schering Pharma Aktiengesellschaft Oxazolidninone zur Behandlung der chronisch obstruktiven Lungenerkrankung (COPD) und/oder Asthma
US12084452B2 (en) 2012-04-26 2024-09-10 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US10793600B2 (en) 2013-07-12 2020-10-06 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
US11225503B2 (en) 2013-07-12 2022-01-18 Helmholtz-Zentrum für Infektionsforschung GmbH Crystobactamides
DE102014108210A1 (de) 2014-06-11 2015-12-17 Dietrich Gulba Rodentizid
US11678659B2 (en) 2014-06-11 2023-06-20 Dietrich Gulba Use as rodenticides of compounds that inhibit blood coagulation
US10519099B2 (en) 2014-11-26 2019-12-31 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
WO2019038405A1 (en) * 2017-08-23 2019-02-28 Helmholtz-Zentrum für Infektionsforschung GmbH NEW CYSTOBACTAMIDE DERIVATIVES
US11034648B2 (en) 2017-08-23 2021-06-15 Helmholtz-Zentrum Für Cystobactamide derivatives
EP4070658A1 (de) 2021-04-06 2022-10-12 BIORoxx GmbH Verwendung von blutgerinnungshemmenden verbindungen als rodentizide
WO2022214485A1 (de) 2021-04-06 2022-10-13 Bioroxx Gmbh Verwendung von blutgerinnungshemmenden verbindungen als rodentizide

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